Mutations associated with long qt syndrome

ABSTRACT

The invention is based, at least in part, on the observation that the presence of particular biomarkers, e.g., particular mutations in any of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes as identified in Tables 1-5 (and, in particular, those identified with an asterisk), is associated with Long QT Syndrome (LQTS).

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/764,841, filed on Apr. 21, 2010, which, in turn, claims priority toU.S. Provisional Application No. 61/214,239, filed Apr. 21, 2009, theentire contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The measurement of the contraction of the heart on an electrocardiogram(ECG) produces a waveform with characteristic elements which correspondto the various stages of contraction. One feature of an ECG is referredto as the QT interval, which represents the time period between theinitiation of ventricular depolarization and completion ofrepolarization. The QT interval varies with the heart rate, age andgender. For example, the QT interval decreases with increasing heartrate. Men generally have shorter QT intervals than women.

Under certain circumstances, the QT interval can be prolonged,increasing the risk of a potentially fatal cardiac arrhythmia, resultingin the inability of the heart to contract effectively, which leads to adecrease in blood flow to periphery, including the brain, and syncope orsudden death. In rare cases, a prolonged QT interval is congenital andusually inherited. In other cases, prolongation of the QT interval isthe result of a neurological disorder, such as stroke. Most frequently,a prolonged QT interval is caused by certain medications.

Congenital long QT syndrome (LQTS) comprises a distinct group of cardiacchannelopathies characterized by QT prolongation on a 12-lead surfaceelectrocardiogram (ECG) and increased risk for syncope, seizures, andsudden cardiac death (SCD) in the setting of a structurally normal heartand otherwise healthy individual. The incidence of LQTS may be as highas 1 in 2500 persons.

Because 2.5% of healthy individuals have a prolonged QT interval and10-15% of LQTS patients have a normal QT interval, LQTS is not easilydiagnosed and subsequently treated.

SUMMARY OF THE INVENTION

The invention is based, at least in part, on the observation that thepresence of particular biomarkers, e.g., particular mutations in any ofthe KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes as identified in Tables1-5 (and, in particular, those identified with an asterisk), areassociated with Long QT Syndrome (LQTS). Accordingly, the presentinvention provides methods and compositions for identifying subjectshaving or susceptible to having LQTS. In addition, the present inventionprovides methods and compositions for predicting the responsiveness of asubject having or predisposed to having LQTS, e.g., a human subject, totreatment for LQTS therapy. The methods include determining the presenceor absence of the biomarkers in a biological sample obtained from thesubject, wherein the presence of at least one of the biomarkers as setforth in any of Tables 1-5 is an indication that the subject willrespond to LQTS therapy, thereby predicting responsiveness of thesubject to the LQTS therapy.

The present invention provides a method for identifying whether asubject suffers from or is predisposed to suffer from congenital long QTsyndrome (LQTS). In one aspect, the method for identifying whether asubject suffers from or is predisposed to suffer from congenital long QTsyndrome (LQTS) includes identifying the presence of at least onebiomarker in a biological sample obtained from the subject, wherein thebiomarker is selected from the group consisting of variants set forth inTables 1-5.

In one embodiment, the biomarker is a variant in at least one of theKCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes. Inanother embodiment, the variant is selected from the group consisting ofa mutation, a missense mutation, a nonsense mutation, an insertion, adeletion, or a frameshift mutation. In another embodiment, the variantdisrupts the open reading frame of the KCNQ1, KCNH2, SCN5A, KCNE1 orKCNE2 genes. In another embodiment, the variant disrupts the canonicalsplice site of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes. In anotherembodiment, the variant disrupts the splice acceptor sequence of theKCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes. In another embodiment, thevariant disrupts the splice donor recognition sequence of the KCNQ1,KCNH2, SCN5A, KCNE1 or KCNE2 genes. In yet another embodiment, thebiomarker is a L266P mutation in KCNQ1, a R518X mutation in KCNQ1, aR594Q mutation in KCNQ1, a G168R mutation in KCNQ1 or a E1784K mutationin SCN5A. In certain embodiments, the biomarker is a nonsense mutationin SCN5A selected from the group consisting of Q73X, R179X, R222X, Y389Xand W1798X. In another embodiment, the biomarker is a frameshiftmutation in SCN5A selected from the group consisting of V850fs+18X andL1786fs+45X.

The present invention also provides a method for predicting therapeuticresponsiveness of a subject having LQTS or susceptible to having LQTS toLQTS therapy. In one aspect, the method includes determining thepresence or absence of at least one biomarker in a biological sampleobtained from the subject, wherein the biomarker is selected from thegroup consisting of variants set forth in Tables 1-5, and wherein thepresence of the at least one biomarker in the sample is an indicationthat the subject will respond to the LQTS therapy, thereby predictingresponsiveness of the subject to the LQTS therapy.

In one embodiment, the LQTS therapy includes a method selected from thegroup consisting of administration of beta receptor blocking agents,implantation of an implantable cardioverter-defibrillator (ICD),potassium supplementation, administration of a sodium channel blockersuch as mexiletine, and amputation of the cervical sympathetic chain.

In one embodiment, determining the presence or absence of at least onebiomarker is accomplished using a technique selected from the groupconsisting of polymerase chain reaction (PCR) amplification reaction,reverse-transcriptase PCR analysis, single-strand conformationpolymorphism analysis (SSCP), mismatch cleavage detection, heteroduplexanalysis, Southern blot analysis, Western blot analysis,deoxyribonucleic acid sequencing, restriction fragment lengthpolymorphism analysis, haplotype analysis, serotyping, and combinationsor sub-combinations thereof, of said sample. In one embodiment, thesample comprises a fluid obtained from the subject. For example, thefluid may be a blood fluid, vomit, intra-articular fluid, saliva, lymph,cystic fluid, urine, fluid collected by bronchial lavage, fluidcollected by peritoneal rinsing, or gynecological fluid. In anotherembodiment, the sample is a blood sample or a component thereof. Inanother embodiment, the sample comprises a tissue or component thereofobtained from the subject. For example, the tissue may be bone,connective tissue, cartilage, lung, liver, kidney, muscle tissue, heart,pancreas, or skin. In one embodiment, the subject is a human.

In one embodiment, the biomarker is a variant in at least one of theKCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes. Inanother embodiment, the variant is selected from the group consisting ofa mutation, a missense mutation, a nonsense mutation, an insertion, adeletion, or a frameshift mutation. In another embodiment, the variantdisrupts the open reading frame of the KCNQ1, KCNH2, SCN5A, KCNE1 orKCNE2 genes. In another embodiment, the variant disrupts the canonicalsplice site of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes. In anotherembodiment, the variant disrupts the splice acceptor sequence of theKCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes. In another embodiment, thevariant disrupts the splice donor recognition sequence of the KCNQ1,KCNH2, SCN5A, KCNE1 or KCNE2 genes. In yet another embodiment, thebiomarker is a L266P mutation in KCNQ1, a R518X mutation in KCNQ1, aR594Q mutation in KCNQ1, a G168R mutation in KCNQ1 or a E1784K mutationin SCN5A. In certain embodiments, the biomarker is a nonsense mutationin SCN5A selected from the group consisting of Q73X, R179X, R222X, Y389Xand W1798X. In another embodiment, the biomarker is a frameshiftmutation in SCN5A selected from the group consisting of V850fs+18X andL1786fs+45X.

The present invention also provides a kit for predicting responsivenessof a subject having LQTS or susceptible to having LQTS to LQTS therapy.In one aspect, the kit includes means for determining the presence orabsence of at least one biomarker in a biological sample obtained fromthe subject, wherein the biomarker is selected from the group consistingof variants set forth in Tables 1-5, and instructions for use of the kitto predict responsiveness of the subject having LQTS to LQTS therapy. Inone embodiment, the kit further includes means for obtaining abiological sample from a subject. In another embodiment, the kit furtherincludes a control sample, for example, a nucleic acid molecule encodingany of SEQ ID NOs:1-5.

The present invention also provides a nucleic acid molecule including avariant of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2genes selected from the group consisting of the variants set forth inTables 1-5.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the reference nucleotide sequence for the KCNQ1 gene (SEQ IDNO:1).

FIG. 2 is the reference nucleotide sequence for the KCNH2 gene (SEQ IDNO:2).

FIG. 3 is the reference nucleotide sequence for the SCN5A gene (SEQ IDNO:3).

FIG. 4 is the reference nucleotide sequence for the KCNE1 gene (SEQ IDNO:4).

FIG. 5 is the reference nucleotide sequence for the KCNE2 gene (SEQ IDNO:5.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based, at least in part, on the observation that thepresence of particular biomarkers, e.g., particular mutations in any ofthe KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes as identified in Tables1-5 (and, in particular, those identified with an asterisk), areassociated with Long QT Syndrome (LQTS). Accordingly, the presentinvention provides methods and compositions for identifying subjectshaving or susceptible to having LQTS. Specifically, by identifying thevariants of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes disclosedherein in biological samples derived from a subject, one can identifythe subject as having or predisposed to having LQTS.

In addition, the present invention provides methods and compositions forpredicting the responsiveness of a subject having or predisposed tohaving LQTS, e.g., a human subject, to treatment for LQTS therapy. Themethods include determining the presence or absence of the biomarkers ina biological sample obtained from the subject, wherein the presence ofat least one of the biomarkers as set forth in any of Tables 1-5 is anindication that the subject will respond to LQTS therapy, therebypredicting responsiveness of the subject to the LQTS therapy.

In order that the present invention may be more readily understood,certain terms are first defined.

As used herein, the term “long QT syndrome” or “LQTS” refers to a rareinborn heart condition in which delayed repolarization of the heartfollowing a heartbeat increases the risk of episodes of torsade depointes (a form of irregular heartbeat that originates from theventricles). These episodes may lead to palpitations, fainting andsudden death due to ventricular fibrillation. Episodes may be provokedby various stimuli, depending on the subtype of the condition.

As used herein, the term “biomarker” is intended to encompass anindicator of a biologic state and includes genes (and nucleotidesequences of such genes), mRNAs (and nucleotide sequences of such mRNAs)and proteins (and amino acid sequences of such proteins). A “biomarkerexpression pattern” is intended to refer to a quantitative orqualitative summary of the expression of one or more biomarkers in asubject, such as in comparison to a standard or a control.

As used herein, biomarkers encompass variants of the KCNQ1, KCNH2,SCN5A, KCNE1 and KCNE2 genes as set forth in Tables 1-5. For example,biomarkers include mutations, missense mutations, nonsense mutations,insertions, deletions, or frameshift mutations in at least one of thesegenes. The biomarkers may serve to disrupt the open reading frame of theKCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes and/or the canonical splicesite, for example, the splice acceptor sequence or splice donorrecognition sequences, of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.

In particular embodiments, the biomarker is any one of a L266P mutationin KCNQ1, a R518X mutation in KCNQ1, a R594Q mutation in KCNQ1, a G168Rmutation in KCNQ1, or a E1784K mutation in SCN5A. Alternatively or inaddition, the biomarker may be a nonsense mutation in SCN5A selectedfrom the group consisting of Q73X, R179X, R222X, Y389X and W1798X. Inother embodiments, the biomarker may be a frameshift mutation in SCN5Aselected from the group consisting of V850fs+18X and L1786fs+45X.

The terms “increased” or “increased expression” and “decreased” or“decreased expression”, with respect to the expression pattern of abiomarker(s), are used herein as meaning that the level of expression isincreased or decreased relative to a constant basal level of expressionof a household, or housekeeping, gene, whose expression level does notsignificantly vary under different conditions. A nonlimiting example ofsuch a household, or housekeeping, gene is GAPDH. Other suitablehousehold, or housekeeping, genes are well-established in the art.

As set forth below, the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genesgenerally encode the major pore-forming alpha subunits of themacromolecular channel complexes Kv7.1 (I_(Ks)), Kv11.1 (I_(Kr)) andNav1.5 (I_(Na)).

As used herein, the term KCNQ1 (LQT1) refers to the gene encoding thevoltage-gated potassium channel KvLQT1 that is highly expressed in theheart. It is believed that the product of the KCNQ1 gene produces analpha subunit that interacts with other proteins (particularly the minKbeta subunit) to create the I_(Ks) ion channel, which is responsible forthe delayed potassium rectifier current of the cardiac action potential.The KCNQ1 gene has been isolated to chromosome 11p15.5. The nucleotidesequence for KCNQ1 is set forth in SEQ ID NO:1.

As used herein, the term KCNH2 (LQT2), also known as human ether-a-go-gorelated gene (HERG), on chromosome 7 is part of the rapid component ofthe potassium rectifying current (I_(Kr)). The I_(Kr) current is mainlyresponsible for the termination of the cardiac action potential, andtherefore the length of the QT interval. Normally functioning HERG geneallows protection against early after depolarizations (EADs).Specifically, KCNH2 refers to the gene encoding potassium voltage-gatedchannel, subfamily H (eag-related), member 2. The nucleotide sequencefor KCNH2 is set forth in SEQ ID NO:2.

As used herein, the term SCN5A (LQT3) (also hH1 and Na_(v)1.5) refers tothe gene encoding sodium channel, voltage-gated, type V, alpha subunit.This gene is located on chromosome 3p21-24, and is known as SCN5A. Thenucleotide sequence for SCN5A is set forth in SEQ ID NO:3. The mutationsslow the inactivation of the Na⁺ channel, resulting in prolongation ofthe Na⁺ influx during depolarization. Paradoxically, the mutant sodiumchannels inactivate more quickly, and may open repetitively during theaction potential.

As used herein, the term KCNE1 refers to the gene encoding potassiumvoltage-gated channel, Isk-related family, member 1 (potassium channelbeta subunit MinK) The nucleotide sequence for KCNE1 is set forth in SEQID NO:4.

As used herein, the term KCNE2 refers to the gene encoding potassiumvoltage-gated channel, Isk-related family, member 2 (potassium channelbeta subunit MiRP1, constituting part of the I_(Kr) repolarizing K⁺current). The nucleotide sequence for KCNE2 is set forth in SEQ ID NO:5.

As used herein, the term “subject” includes humans, and non-humananimals amenable to LQTS therapy, e.g., preferably mammals, such asnon-human primates, sheep, dogs, cats, horses and cows.

As used herein, the term “treatment regimen” is intended to refer to oneor more parameters selected for the treatment of a subject, e.g., byadministering beta receptor blocking agents, which parameters caninclude, but are not necessarily limited to, the type of agent chosenfor administration, the dosage, the formulation, the route ofadministration and the frequency of administration.

LQTS therapy includes, but is not limited to, administration of betareceptor blocking agents, implantation of an implantablecardioverter-defibrillator (ICD), potassium supplementation,administration of a sodium channel blocker such as mexiletine, andamputation of the cervical sympathetic chain.

The term “predicting responsiveness to LQTS therapy”, as used herein, isintended to refer to an ability to assess the likelihood that treatmentof a subject with LQTS therapy will or will not be effective in (e.g.,provide a measurable benefit to) the subject. In particular, such anability to assess the likelihood that treatment will or will not beeffective typically is exercised before LQTS treatment is begun in thesubject. However, it is also possible that such an ability to assess thelikelihood that treatment will or will not be effective can be exercisedafter treatment has begun but before an indicator of effectiveness(e.g., an indicator of measurable benefit) has been observed in thesubject.

The present invention is further illustrated by the following exampleswhich should not be construed as further limiting. The contents of allreferences, patents and published patent applications cited throughoutthis application are expressly incorporated herein by reference in theirentirety.

EXAMPLES Example 1 Identification of Biomarkers Associated with LOTS

Between May 2004 and October 2008, 2500 unrelated patients (1515females, average age at testing=26±17 years and 985 males, average ageat testing=19±15 years) were tested for LQTS by PGxHealth, LLC in NewHaven, Conn. Patient genomic DNA was analyzed for mutations in all 60translated exons and their canonical splice site regions of KCNQ1,KCNH2, SCN5A, KCNE1, and KCNE2 using polymerase chain reaction (PCR) andautomated DNA sequencing. All PCR primers were designed with specialcare to avoid the phenomenon of allelic dropout, which can lead to afalse negative genetic test result. Insertions and deletions that spanan amplicon or interfere with amplification are not detected. Referencesequences for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 are provided as,respectively, SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, andSEQ ID NO:5.

All putative LQTS-associated mutations and other variants were denotedusing known and accepted nomenclature. For example, the single letteramino acid code was used to designate missense mutations (single aminoacid substitutions) using the L250P format. Here, at amino acid position250, the ‘wild type’ amino acid (L=leucine) is replaced by a proline (P)on one of the chromosomes. Frameshift mutations resulting fromnucleotide insertions or deletions were annotated using the R174fs+105Xformat. Here, R174 represents the last properly encoded amino acidfollowed by a frameshift (fs) in the coding sequence resulting in 105miscoded amino acids prior to reaching a stop codon (X) resulting in atruncated protein containing a total of 279 amino acids.

A substitution of either the first two or the last two nucleotides of aparticular exon has the capacity to alter proper mRNA splicing,regardless of whether the nucleotide substitution codes for a differentamino acid (missense mutation), produces a stop codon (nonsensemutation) or does not alter the open reading frame at all (i.e., asynonymous or silent single nucleotide substitution). As such, mutationsinvolving this exonic portion of the “splice site” were considered aspossible splicing mutations in this study and annotated as either“missense/splice,” “nonsense/splice,” or “silent/splice” mutations inorder to distinguish them from intronic mutations predicted to disruptsplicing.

Topological placement of the mutations was done using a combination ofSwissprot (http://ca.expasy.org/uniprot/) and recent studies of thelinear topologies for each of the three main pore-forming alphasubunits. The Swissprot database provides generally accepted residueranges corresponding with each ion-channel region and specializedsub-regions. To be considered as a potential LQTS-causing mutation, thevariant should disrupt the open reading frame (i.e., missense, nonsense,insertion/deletion, or frameshift mutations) or the canonical splicesite (splice acceptor or splice donor recognition sequences). Inaddition to the exonic splice sites described above, the canonicalacceptor splice site was defined as the seven intronic nucleotides,except the fourth, preceding an exon (designated as IVS−1, −2, −3, −5,−6, or −7) and the donor splice site as the first five intronicnucleotides following an exon (designated as IVS+1, +2, +3, +4, or +5).Hence, single nucleotide substitutions that did not change the openreading frame (i.e., synonymous single nucleotidepolymorphisms/variants) and intronic nucleotide substitutions locatedoutside of the canonical splice site recognition sequence (i.e., beyondIVS−5 or IVS+5) were excluded from consideration.

Additionally, the candidate mutation must not have been observed in apanel of now over 1300 ostensibly healthy volunteers (>2600 referencealleles). As such, the sole or concurrent presence of common or rarenon-synonymous single nucleotide polymorphisms like P448R-KCNQ1,R176W-KCNH2, H558R-SCN5A, D85N-KCNE1, or Q9E-KCNE2 would not bedesignated as a pathogenic mutation resulting in LQT1, LQT2, LQT3, LQT5,or LQT6 respectively, despite there being evidence of slight abnormalityor risk associated with some of these. Further, such polymorphisms wouldnot be counted towards the assignment of compound or multiple mutationstatus to an individual.

The genes causative of the major LQTS subtypes encode ion channelsubunits with regions that span the cell membrane to allow ions to flowin or out of the cell, as well as functional domains that regulate thepassage of these ions. The probability that a novel missense mutationidentified in a LQTS patient is pathogenic is directly related to theposition of the mutation within the protein. The protein encoded byKCNQ1 has a transmembrane domain region that consist of 6 transmembranespanning domains annotated S1 through S6, and each domain is connectedby a small linker region named according the domains that it connects(i.e., the first linker domain is named S1/S2). The entire transmembranedomain region of KCNQ1 protein is flanked by non-transmembrane regionsreferred to as the N-terminus and C-terminus Within the C-terminusregion of KCNQ1, a regulatory domain called the Subunit Assembly Region(SAR) exists. Similar for the proteins encoded by KCNH2, SCN5A, KCNE1,and KCNE2, transmembrane domain regions are also flanked by N-terminiand C-termini. Specifically, KCNH2 protein has 6 transmembrane spanningdomains referred to S1 through S6, linker domains connecting thesestransmembrane spanning domains, regulatory domains within the N-terminuscalled the Per-Arnt-Sim (PAS) domain and the PAS-associated C-terminaldomain (PAC), and one regulatory domain within the C-terminus called theCyclic nucleotide binding domain (cNBD). The protein region in KCNH2that is located between and including the S5 and S6 transmembranedomains is specifically referred to as the Pore region. SCN5A proteinconsists of 4 sets of the 6 transmembrane spanning domains referred toas DI through DIV and linker domains connecting each transmembranespanning segment. The proteins encoded by KCNE1 and KCNE1 each contain asingle transmembrane domain flanked by N- and C-termini. The specificlocation of a mutation in the complex of structure of these LQTScausative genes is directly related to the likelihood of itspathogenicity. Missense mutations that localize to the pore domain,transmembrane-spanning domains (e.g. S1-S6), or other criticalsubdomains (i.e., PAS, PAC, cNBD, and SAR) confer a high probability forcausing LQTS.

Overall, 903/2500 (36%) unrelated cases had a positive genetic test withthe identification of a putative LQTS-causing mutation that was absentin over 2600 reference alleles. Among the 903 genotype-positivepatients, 821 (91%) had a single mutation: 386 in KCNQ1 (43%), 288 inKCNH2 (32%), 115 in SCN5A (13%), 24 in KCNE1, and 8 in KCNE2.

The remaining 82 patients (9%) had >1 mutation including 30 cases withmultiple mutations in the same gene: KCNQ1 (19), KCNH2 (3), SCN5A (6),KCNE1 (1), and KCNE2 (1). Fifty-two cases were compound heterozygouswith mutations in >1 gene.

In total, the 903 genotype-positive cases stemmed from 562 distinctLQTS-causing mutations: 199 distinct mutations in KCNQ1, 226 in KCNH2,110 in SCN5A, 18 in KCNE1, and 9 in KCNE2 (Tables 1-5). Notably, overhalf of the mutations (336/562, 60%) were novel to this cohort including92 in KCNQ1, 159 in KCNH2, and 70 in SCN5A. The vast majority (76%) ofthe mutations were observed in a single index case while 134 mutations(24%) were observed more than once in this cohort. The five mostcommonly observed LQTS-causing mutations were L266P-KCNQ1 seen in 30unrelated patients, R518X-KCNQ1 in 24, R594Q-KCNQ1 in fifteen,G168R-KCNQ1 in fifteen, and E1784K-SCN5A in fifteen unrelated patients.

Overall, the majority of mutations (394/562, 70%) were missense, while85 (15%) were frame-shift mutations, 33 (5.9%) involved canonical splicesites, 33 (5.9%) were nonsense mutations, and 17 (3%) were in-frameinsertions/deletions. While 64% of all frame-shift mutations wereidentified in KCNH2 (representing 24% of all KCNH2 mutations), 76% ofthe splice-site mutations involved KCNQ1 (representing 12.5% of allKCNQ1 mutations). As will be discussed below, five nonsense (Q73X,R179X, R222X, Y389X, and W1798X) and two frame-shift mutations(V850fs+18X and L1786fs+45X) were identified in SCN5A.

For mutations in KCNQ1, 102/199 (51%) localized to the transmembranespanning and pore-forming domains, thirteen (6.5%) to the specializedSubunit Assembly Region, 15 (7.5%) in the N-terminus, and 69 (35%)resided in the C-terminus (Table 1). For mutations in KCNH2, 73/226(32%) localized to the transmembrane spanning and pore-forming domains,18 (8%) in the N-terminal PAS/PAC regulatory domains, 47 (21%) elsewherein the N-terminus, 18 (8%) in the C-terminal cyclic nucleotide domain(cNBD), and 70 (31%) elsewhere in the C-terminus (Table 2). Among the108 mutations in SCN5A, eleven (10%) localized to the N-terminus, 46(43%) to the transmembrane spanning and pore-forming domains, 38 (35%)to the inter-domain cytoplasmic linkers (DI-DII, DII-DIII, andDIII-DIV), and thirteen (12%) to the C-terminus (Table 3).

TABLE 1 Summary of putative LQT1-associated mutations in KCNQ1 Positionin SEQ Mutation No. of Region Nucleotide Variant ID NO: 1 Type Locationpatients Exon 1 5 C > T A2V* 80533 Missense N-Terminal 1 Exon 1 19 C > TP7S* 80547 Missense N-Terminal 1 Exon 1 108insT F36fs + 247X* 80636Frame shift N-Terminal 1 Exon 1 136 G > A A46T 80664 Missense N-Terminal2 Exon 1 153 C > G Y51X 80681 Nonsense N-Terminal 1 Exon 1 176delCA58fs + 26X* 80704 Frame shift N-Terminal 1 Exon 1 190_210del 64_70del80718 In-frame N-Terminal 3 CCTGCG PASPAAP* del TCCCCG GCCGCG CCC Exon 1197 C > T S66F* 80725 Missense N-Terminal 1 Exon 1 200_210del S66fs +213X* 80728 Frame shift N-Terminal 1 CGGCCG CGCCC Exon 1 217 C > A P73T80745 Missense N-Terminal 4 Exon 1 242_264del G80fs + 151X* 80770 Frameshift N-Terminal 1 CGCGGC CGCCGG TGAGCC TA GACinsG CGCCCG CGG Exon 1273_299del V91fs + 136X* 80801 Frame shift N-Terminal 1 CTCCAT CTACAGCACGCG CC GCCCGG TinsGG Exon 1 332 A > G Y111C 80860 Missense N-Terminal5 Exon 1 350 C > T P117L 80878 Missense N-Terminal 1 Exon 1 365insTK121fs + 162X* 80893 Frame shift N-Terminal 2 Exon 1 381 C > A F127L*80909 Missense S1 Domain 1 Intron 1 386 + 1 80915 Splice site S1 Domain1 G > A Exon 2 397 G > A V133I 163375 Missense S1 Domain 1 Exon 2 401T > C L134P* 163379 Missense S1 Domain 1 Exon 2 403delG L134fs + 101X*163381 Frame shift S1 Domain 1 Exon 2 430 A > G T144A 163408 MissenseS1/S2 1 Exon 2 451_452del A150fs + 132X 163429 Frame shift S2 Domain 1CT Exon 2 458 C > T T153M* 163436 Missense S2 Domain 1 Intron 2 477 + 1163456 Splice site S2 Domain 1 G > A Intron 2 477 + 5 163460 Splice siteS2 Domain 1 G > C Intron 2 477 + 5 163460 Splice site S2 Domain 4 G > AExon 3 479 A > T E160V* 206043 Missense/ S2 Domain 1 Splice Exon 3 484G > A V162M* 206048 Missense S2 Domain 1 Exon 3 488delT V162fs + 73X206052 Frame shift S2 Domain 1 Exon 3 502 G > A G168R 206066 Missense S2Domain 15 Exon 3 502 G > C G168R 206066 Missense S2 Domain 4 Exon 3504delG G168fs + 67X* 206068 Frame shift S2 Domain 1 Exon 3 513 C > GY171X 206077 Nonsense S2/S3 1 Exon 3 514 G > A V172M 206078 MissenseS2/S3 2 Exon 3 520 C > T R174C 206084 Missense S2/S3 1 Exon 3 521 G > AR174H 206085 Missense S2/S3 1 Exon 3 524_534del R174fs + 105X* 206088Frame shift S2/S3 1 TCTGGT CCGCC Exon 3 532 G > A A178T 206096 MissenseS2/S3 1 Exon 3 535 G > A G179S 206099 Missense S2/S3 2 Exon 3 550 T > CY184H* 206114 Missense S2/S3 1 Exon 3 556 G > C G186R* 206120 MissenseS2/S3 1 Exon 3 564 G > A W188X* 206128 Nonsense S2/S3 1 Exon 3 569 G > AR190Q 206133 Missense S2/S3 3 Exon 3 569 G > T R190L* 206133 MissenseS2/S3 1 Exon 3 573_577del L191fs + 90X 206137 Frame shift S2/S3 4 GCGCTExon 3 583 C > T R195W* 206147 Missense S2/S3 2 Exon 3 585delG R195fs +40X 206149 Frame shift S2/S3 4 Exon 3 592 A > G I198V* 206156 MissenseS3 Domain 1 Exon 3 595 T > G S199A* 206159 Missense S3 Domain 1 Exon 3604 G > A D202N 206168 Missense/ S3 Domain 1 Splice Intron 3 605-2206737 Splice site S3 Domain 1 A > G Exon 4 612 C > G I204M 206746Missense S3 Domain 1 Exon 4 643 G > A V215M 206777 Missense S3 Domain 1Exon 4 671 C > T T224M* 206805 Missense S3/S4 1 Exon 4 674 C > T S225L206808 Missense S3/S4 8 Exon 5 691 C > T R231C 207434 Missense S4 Domain1 Exon 5 692 G > A R231H 207435 Missense S4 Domain 1 Exon 5 704 T > AI235N 207447 Missense S4 Domain 2 Exon 5 722 T > G V241G* 207465Missense S4 Domain 1 Exon 5 724 G > A D242N 207467 Missense S4 Domain 4Exon 5 727delC D242fs + 19X* 207470 Frame shift S4 Domain 1 Exon 5 727C > T R243C 207470 Missense S4 Domain 1 Exon 5 749 T > C L250P* 207492Missense S4/S5 1 Exon 5 760 G > A V254M 207503 Missense S4/S5 10 Exon 5775 C > T R259C 207518 Missense S4/S5 5 Exon 5 776_780dup H258fs + 5X*207519 Frame shift S4/S5 1 CCACC Exon 5 776 G > T R259L 207519 MissenseS4/S5 1 Exon 6 781 G > C E261Q* 208260 Missense/ S4/S5 1 Splice Exon 6781 G > T E261X* 208260 Nonsense/ S4/S5 1 Splice Exon 6 784 C > G L262V208263 Missense S5 domain 1 Exon 6 796delC T265fs + 22X 208275 Frameshift S5 domain 3 Exon 6 797 T > C L266P 208276 Missense S5 domain 30Exon 6 803 T > G I268S* 208282 Missense S5 domain 1 Exon 6 805 G > AG269S 208284 Missense S5 domain 10 Exon 6 806 G > A G269D 208285Missense S5 domain 4 Exon 6 815 G > A G272D 208294 Missense S5 domain 1Exon 6 817 C > T L273F 208296 Missense S5 domain 7 Exon 6 820 A > GI274V 208299 Missense S5 domain 1 Exon 6 829 T > C S277P* 208308Missense S5 domain 1 Exon 6 830 C > T S277L 208309 Missense S5 domain 2Exon 6 839 T > A V280E 208318 Missense S5 domain 1 Exon 6 842 A > GY281C 208321 Missense S5 domain 1 Exon 6 845 T > C L282P* 208324Missense S5 domain 1 Exon 6 848 C > G A283G* 208327 Missense S5/pore 2Exon 6 862_880del A287fs + 59X* 208341 Frame shift S5/pore 2 GTGAACGAGTCA GGCCGCG Exon 6 875 G > A G292D 208354 Missense S5/pore 1 Exon 6877 C > T R293C 208356 Missense S5/pore 4 Exon 6 905 C > T A302V 208384Missense Pore 1 Exon 6 905 C > A A302E* 208384 Missense Pore 1 Exon 6908 T > C L303P* 208387 Missense Pore 1 Exon 6 913 T > C W305R* 208392Missense Pore 1 Exon 6 914 G > C W305S 208393 Missense Pore 1 Exon 6 914G > A W305X 208393 Nonsense Pore 1 Exon 6 916 G > A G306R 208395Missense Pore 1 Exon 6 916 G > C G306R 208395 Missense Pore 1 Exon 7 935C > T T312I 218864 Missense Pore 2 Exon 7 940 G > A G314S 218869Missense Pore 7 Exon 7 940 G > T G314C 218869 Missense Pore 1 Exon 7 944A > G Y315C 218873 Missense Pore 4 Exon 7 947 G > T G316V* 218876Missense Pore 1 Exon 7 958 C > T P320S* 218887 Missense Pore 1 Exon 7964 A > G T322A 218893 Missense Pore/S6 2 Exon 7 965 C > T T322M 218894Missense Pore/S6 4 Exon 7 973 G > A G325R 218902 Missense Pore/S6 6 Exon7 1016 T > A F339Y* 218945 Missense S6 1 Exon 7 1017_1019 340delF 218946In-frame S6 1 delCTT del Exon 7 1022 C > A A341E 218951 Missense S6 4Exon 7 1022 C > T A341V 218951 Missense S6 8 Exon 7 1022 C > G A341G*218951 Missense S6 1 Exon 7 1024 C > T L342F 218953 Missense S6 2 Exon 71028 C > T P343L 218957 Missense S6 1 Exon 7 1031 C > T A344V 218960Missense/ S6 1 Splice Exon 7 1032 G > A A344A 218961 Silent/ S6 10Splice Intron 7 1032 + 1 218962 Splice site S6 1 G > T Intron 7 1032 + 1218962 Splice site S6 2 G > A Intron 7 1032 + 2 218963 Splice site S6 1T > C Intron 7 1032 + 5 218966 Splice site S6 1 G > T Exon 8 1046 C > AS349X 220642 Nonsense C-Terminal 1 Exon 8 1048 G > A G350R 220644Missense C-Terminal 1 Exon 8 1052 T > C F351S 220648 Missense C-Terminal1 Exon 8 1061 A > G K354R* 220657 Missense C-Terminal 1 Exon 8 1066 C >T Q356X 220662 Nonsense C-Terminal 1 Exon 8 1075 C > T Q359X* 220671Nonsense C-Terminal 4 Exon 8 1079 G > T R360M* 220675 MissenseC-Terminal 2 Exon 8 1085 A > G K362R 220681 Missense C-Terminal 5 Exon 81093 A > C N365H* 220689 Missense C-Terminal 1 Exon 8 1096 C > T R366W220692 Missense C-Terminal 8 Exon 8 1097 G > A R366Q 220693 MissenseC-Terminal 1 Exon 8 1121 T > A L374H 220717 Missense C-Terminal 1 Intron8 1128 + 1 220725 Splice site C-Terminal 1 G > A Intron 8 1128 + 1220725 Splice site C-Terminal 1 G > T Intron 8 1128 + 5 220729 Splicesite C-Terminal 1 G > A Exon 9 1135 T > G W379G* 222994 MissenseC-Terminal 1 Exon 9 1153 G > A E385K* 223012 Missense C-Terminal 1 Exon9 1165 T > C S389P* 223024 Missense C-Terminal 1 Exon 9 1171_1173391dupS* 223030 In-frame C-Terminal 1 dupCTT ins Exon 9 1177_1179393dupW* 223036 In-frame C-Terminal 3 dupTGG ins Exon 9 1189 C > T R397W223048 Missense C-Terminal 3 Exon 9 1193 A > G K398R* 223052 MissenseC-Terminal 1 Exon 9 1196_1197 K398fs + 19X* 223055 Frame shiftC-Terminal 1 delCCinsA Exon 9 1202insC P400fs + 61X* 223061 Frame shiftC-Terminal 1 Intron 9 1251 + 2 223112 Splice site C-Terminal 1 T > CExon 1265delA K421fs + 9X* 224144 Frame shift C-Terminal 2 10 Exon 1338C > G D446E* 224217 Missense C-Terminal 2 10 Exon 1343 C > T P448L*224222 Missense C-Terminal 1 10 Exon 1351 C > T R451W* 224230 MissenseC-Terminal 1 10 Exon 1378 G > A G460S 224257 Missense C-Terminal 1 10Exon 1430 C > T P477L* 297413 Missense C-Terminal 1 11 Exon 1462delGE487fs + 9X* 297445 Frame shift C-Terminal 1 11 Exon 1486_1487 T495fs +18X 297469 Frame shift C-Terminal 1 11 delCT Exon 1513 C > T Q505X*297496 Nonsense/ C-Terminal 1 11 Splice Intron 1515-2 del 404258 Splicesite C-Terminal 1 11 AG Exon 1531 C > T R511W* 404276 MissenseC-Terminal 1 12 Exon 1552 C > T R518X 404297 Nonsense C-Terminal 24 12Exon 1553 G > A R518Q* 404298 Missense C-Terminal 1 12 Exon 1559 T > GM520R 404304 Missense C-Terminal 3 12 Exon 1565 A > C Y522S* 404310Missense C-Terminal 1 12 Exon 1571 T > G V524G 404316 MissenseC-Terminal 1 12 Exon 1573 G > A A525T 404318 Missense C-Terminal 1 12Exon 1574 C > T A525V 404319 Missense C-Terminal 1 12 Exon 1588 C > TQ530X 404333 Nonsense C-Terminal 10 12 Exon 1591 C > T Q531X* 411376Nonsense/ C-Terminal 1 13 Splice Exon 1597 C > T R533W 411382 MissenseC-Terminal 2 13 Exon 1615 C > T R539W 411400 Missense C-Terminal 6 13Exon 1616 G > A R539Q* 411401 Missense C-Terminal 1 13 Exon 1621 G > AV541I* 411406 Missense C-Terminal 1 13 Exon 1627 G > A E543K* 411412Missense C-Terminal 1 13 Exon 1637 C > T S546L 411422 MissenseC-Terminal 4 13 Exon 1640 A > G Q547R* 411425 Missense C-Terminal 1 13Exon 1663 C > A R555S* 411448 Missense C-Terminal 1 13 Exon 1663 C > TR555C 411448 Missense C-Terminal 4 13 Exon 1664 G > A R555H 411449Missense C-Terminal 1 13 Exon 1669 A > G K557E 411454 MissenseC-Terminal 1 13 Intron 1686-1 412401 Splice site C-Terminal 1 13 G > TExon 1696 T > C S566P* 412412 Missense C-Terminal 1 14 Exon 1697 C > TS566F 412413 Missense C-Terminal 5 14 Exon 1697 C > A S566Y 412413Missense C-Terminal 2 14 Exon 1700 T > C I567T 412416 MissenseC-Terminal 3 14 Exon 1702 G > A G568R 412418 Missense C-Terminal 7 14Exon 1705 A > G K569E* 412421 Missense C-Terminal 1 14 Exon 1712 C > TS571L* 412428 Missense C-Terminal 1 14 Exon 1760 C > T T587M 413419Missense C-Terminal 2 15 Exon 1766 G > A G589D 413425 Missense SAR 1 15Exon 1771 C > T R591C 413430 Missense SAR 1 15 Exon 1772 G > A R591H413431 Missense SAR 7 15 Exon 1781 G > A R594Q 413440 Missense SAR 15 15Exon 1781 G > C R594P 413440 Missense SAR 1 15 Exon 1786_1788 596delE*413447 In-frame SAR 1 15 delAGA del Exon 1786 G > A E596K* 413445Missense SAR 1 15 Exon 1794 G > A K598K* 413453 Silent/ SAR 2 15 SpliceIntron 1794 + 1 413454 Splice site SAR 1 15 G > T Exon 1799 C > T T600M483187 Missense SAR 3 16 Exon 1811insC D603fs + 47X* 483199 Frame shiftSAR 1 16 Exon 1831 G > A D611N* 483219 Missense SAR 1 16 Exon 1842_1844614delH* 483230 In-frame SAR 1 16 delCCA del Exon 1876 G > A G626S483264 Missense C-Terminal 1 16 Exon 1894insC P631fs + 19X 483282 Frameshift C-Terminal 1 16 Exon 1903 G > A G635R* 483291 Missense C-Terminal2 16 Exon 1986 C > G Y662X* 483374 Nonsense C-Terminal 1 16 *denotes anovel variant, unique to this cohort. Deletion variants are indicated asdel, insertions as ins, duplications as dup, and frameshift mutationsare annotated for example as R174fs + 105X format, where R174 representsthe last properly encoded amino acid followed by a frameshift (fs) inthe coding sequence resulting in 105 miscoded amino acids leading up toa premature stop codon (X). SAR = subunit assembly region.

TABLE 2 Summary of putative LQT2-associated mutations in KCNH2 Positionin SEQ ID Mutation No. of Region Nucleotide Variant NO: 2 Type Locationpatients Exon 1 47 A > C D16A* 4060 Missense N-Terminal 1 Exon 1 58 C >G R20G* 4071 Missense N-Terminal 1 Exon 1 73delC G24fs + 34X* 4086 Frameshift N-Terminal 1 Exon 2 87 C > A F29L 6996 Missense N-Terminal 1 Exon2 89 T > C I30T* 6998 Missense N-Terminal 1 Exon 2 94 G > A A32T* 7003Missense N-Terminal 1 Exon 2 100delG N33fs + 25X* 7009 Frame shiftN-Terminal 1 Exon 2 121 G > T V41F* 7030 Missense PAS 1 Exon 2 133 A > TN45Y* 7042 Missense PAS 1 Exon 2 158 G > A G53D* 7067 Missense PAS 1Exon 2 160 T > C Y54H* 7069 Missense PAS 1 Exon 2 169 G > C A57P* 7078Missense PAS 1 Exon 2 192 C > G C64W* 7101 Missense PAS 1 Exon 2 208 C >A H70N* 7117 Missense PAS 1 Exon 2 209 A > G H70R 7118 Missense PAS 4Exon 2 215_239delCGCG 72_80delPRTQ 7124 In-frame indel N-Terminal 1CACGCAGCGCC RRAAAinsRP GCGCTGCCGCin V* sGGCCCGT Exon 2 215 C > T P72L*7124 Missense N-Terminal 1 Exon 2 215 C > A P72Q 7124 MissenseN-Terminal 10 Exon 2 219_226del R73fs + 39X* 7128 Frame shift N-Terminal1 CACGCAGCinsT Exon 2 220 A > C T74P* 7129 Missense N-Terminal 1 Exon 2221 C > G T74R* 7130 Missense N-Terminal 1 Exon 2 221 C > T T74M 7130Missense N-Terminal 1 Exon 2 234_241delTGCC A78fs + 62X* 7143 Frameshift N-Terminal 2 GCGC Exon 2 254 C > T A85V 7163 Missense N-Terminal 1Exon 2 257 T > C L86P* 7166 Missense N-Terminal 1 Exon 2 281 T > G V94G*7190 Missense PAC 1 Exon 2 298 C > T R100W* 7207 Missense PAC 2 Exon 2299 G > A R100Q 7208 Missense PAC 1 Exon 2 305 A > C D102A* 7214Missense PAC 1 Exon 3 317 T > A F106Y* 10326 Missense PAC 1 Exon 3 322T > C C108R* 10331 Missense PAC 1 Exon 3 340 C > T P114S 10349 MissensePAC 1 Exon 3 374 T > G F125C* 10383 Missense PAC 1 Exon 3 376_387delATCC126_129del 10385 In-frame del PAC 1 TCAATTTC ILNF* Exon 3 422 C > TP141L* 10431 Missense PAC 2 Exon 3 446 G > C G149A* 10455 MissenseN-Terminal 1 Exon 3 447insG P151fs + 179X 10456 Frame shift N-Terminal 1Exon 3 454insC P151fs + 179X 10463 Frame shift N-Terminal 1 Intron 3 473− 7C > A 11544 Splice site N-Terminal 1 Exon 4 491 G > A R164H* 11569Missense N-Terminal 2 Exon 4 506delC P168fs + 4X* 11584 Frame shiftN-Terminal 1 Exon 4 545 C > A S182X 11623 Nonsense N-Terminal 2 Exon 4548delG S182fs + 17X* 11626 Frame shift N-Terminal 1 Exon 4569_586insGCGC 190_195insGA 11647 In-frame ins N-Terminal 1 GGGCGGCGCGGGGAG* GCG Exon 4 640 G > T E214X* 11718 Nonsense N-Terminal 1 Exon 4 652A > G M218V* 11730 Missense N-Terminal 1 Exon 4 685 G > T E229X 11763Nonsense N-Terminal 1 Exon 4 724 C > G R242G* 11802 Missense N-Terminal1 Exon 4 759_760delGC A253fs + 76X* 11837 Frame shift N-Terminal 1 Exon4 775 G > A D259N 11853 Missense N-Terminal 1 Exon 4 830 C > A A277D*11908 Missense N-Terminal 1 Exon 4 872 T > C M291T* 11950 MissenseN-Terminal 2 Exon 4 902 G > T R301L* 11980 Missense N-Terminal 1 Exon 5925delC M308fs + 50X* 12559 Frame shift N-Terminal 2 Exon 5 934 C > TR312C 12568 Missense N-Terminal 1 Exon 5 940 G > A G314S* 12574 MissenseN-Terminal 1 Exon 5 967 G > A D323N* 12601 Missense N-Terminal 1 Exon 5982 C > T R328C 12616 Missense N-Terminal 4 Exon 5 1006delA Q335fs +23X* 12640 Frame shift N-Terminal 1 Exon 5 1096 C > T R366X 12730Nonsense N-Terminal 2 Exon 5 1128 G > A Q376Q 12762 Silent/SpliceN-Terminal 3 Exon 6 1138delC S379fs + 53X* 15872 Frame shift N-Terminal1 Exon 6 1139delT S379fs + 53X* 15873 Frame shift N-Terminal 1 Exon 61193 G > A W398X* 15927 Nonsense N-Terminal 1 Exon 6 1205 A > G H402R*15939 Missense N-Terminal 1 Exon 6 1262 C > T T421M 15996 Missense S1Domain 1 Exon 6 1266delT A422fs + 10X* 16000 Frame shift S1 Domain 1Exon 6 1280 A > G Y427C* 16014 Missense S1/S2 1 Exon 6 1293 C > A F431L*16027 Missense S1/S2 1 Exon 6 1316delG E438fs + 81X* 16050 Frame shiftS1/S2 1 Exon 6 1319 C > T P440L* 16053 Missense S1/S2 1 Exon 6 1341 C >A Y447X 16075 Nonsense S1/S2 1 Exon 6 1348 C > T Q450X* 16082 NonsenseS1/S2 1 Exon 6 1352 C > T P451L 16086 Missense S2 Domain 1 Exon 61379delA V459fs + 60X 16113 Frame shift S2 Domain 3 Exon 6 1396 G > TD466Y* 16130 Missense S2 Domain 1 Exon 6 1418 C > A T473N* 16152Missense S2/S3 1 Exon 6 1419_1472delCAC T473fs + 26X* 16153 Frame shiftS2/S3 1 CTACGTCAATG CCAACGAGGAG GTGGTCAGCCA CCCCGGCCGCA TCGCCGTinsA Exon6 1424 A > G Y475C 16158 Missense S2/S3 1 Exon 6 1426 G > A V476I* 16160Missense S2/S3 1 Exon 6 1468 G > A A490T 16202 Missense S2/S3 1 Exon 61478 A > G Y493C 16212 Missense S2/S3 2 Exon 6 1478 A > C Y493S* 16212Missense S2/S3 1 Exon 6 1501 G > A D501N 16235 Missense S3 Domain 2Intron 6 1557 + 1 G > C 16292 Splice site S3/S4 2 Exon 7 1591 C > TR531W* 16914 Missense S4 Domain 2 Exon 7 1600 C > T R534C 16923 MissenseS4 Domain 4 Exon 7 1601 G > T R534L 16924 Missense S4 Domain 1 Exon 71613_1619delAG R537fs + 24X 16936 Frame shift S4 Domain 1 CTGGA Exon 71655 T > C L552S 16978 Missense S5 domain 2 Exon 7 1673 C > A A558E*16996 Missense S5 domain 1 Exon 7 1681 G > A A561T 17004 Missense S5domain 1 Exon 7 1682 C > T A561V 17005 Missense S5 domain 6 Exon 7 1685A > G H562R* 17008 Missense S5 domain 2 Exon 7 1688 G > A W563X 17011Nonsense S5 domain 1 Exon 7 1693 G > A A565T* 17016 Missense S5 domain 1Exon 7 1704 G > A W568X* 17027 Nonsense S5 domain 1 Exon 7 1714 G > AG572S 17037 Missense S5/Pore 2 Exon 7 1715 G > T G572V* 17038 MissenseS5/Pore 1 Exon 7 1715 G > A G572D 17038 Missense S5/Pore 1 Exon 7 1742C > A S581X* 17065 Nonsense S5/Pore 1 Exon 7 1744 C > T R582C 17067Missense S5/Pore 1 Exon 7 1750 G > A G584S 17073 Missense S5/Pore 4 Exon7 1750 G > C G584R* 17073 Missense S5/Pore 1 Exon 7 1755 G > T W585C17078 Missense S5/Pore 1 Exon 7 1778 T > A I593K* 17101 Missense S5/Pore1 Exon 7 1781 G > A G594D* 17104 Missense S5/Pore 2 Exon 7 1787 C > AP596H* 17110 Missense S5/Pore 1 Exon 7 1787 C > T P596L 17110 MissenseS5/Pore 1 Exon 7 1790 A > G Y597C 17113 Missense S5/Pore 1 Exon 7 1797C > A S599R* 17120 Missense S5/Pore 1 Exon 7 1801 G > T G601C 17124Missense S5/Pore 1 Exon 7 1801 G > A G601S 17124 Missense S5/Pore 2 Exon7 1810 G > A G604S 17133 Missense S5/Pore 2 Exon 7 1813 C > T P605S*17136 Missense S5/Pore 1 Exon 7 1814 C > T P605L* 17137 Missense S5/Pore1 Exon 7 1826 A > G D609G 17149 Missense S5/Pore 1 Exon 7 1838 C > TT613M 17161 Missense Pore 7 Exon 7 1841 C > T A614V 17164 Missense Pore6 Exon 7 1847 A > G Y616C* 17170 Missense Pore 1 Exon 7 1877 G > AG626D* 17200 Missense Pore 1 Exon 7 1882 G > A G628S 17205 Missense Pore4 Exon 7 1886 A > T N629I* 17209 Missense Pore 2 Exon 7 1886 A > G N629S17209 Missense Pore 1 Exon 7 1901 C > T T634I* 17224 Missense Pore/S6 1Exon 7 1903 A > G N635D* 17226 Missense Pore/S6 1 Exon 7 1905 C > GN635K* 17228 Missense Pore/S6 1 Exon 7 1911 G > C E637D 17234 MissensePore/S6 1 Exon 7 1913_1915del 638delK* 17236 In-frame del Pore/S6 1 AGAExon 7 1914 G > T K638N* 17237 Missense Pore/S6 1 Exon 7 1930 G > CV644L* 17253 Missense S6 1 Exon 7 1930 G > T V644F 17253 Missense S6 1Exon 7 1935 G > A M645I* 17258 Missense S6 1 Exon 7 1942 G > A G648S*17265 Missense S6 1 Exon 8 1955del M651fs + 68X* 17605 Frame shift S6 1ATGCTAinsT Exon 8 1956delT M651fs + X* 17606 Frame shift S6 1 Exon 81969 G > C G657R* 17619 Missense S6 1 Exon 8 1969 G > A G657S* 17619Missense S6 1 Exon 8 1979 C > T S660L 17629 Missense C-Terminal 3 Exon 81985 T > C I662T* 17635 Missense C-Terminal 1 Exon 8 2033 T > C L678P*17683 Missense C-Terminal 1 Exon 8 2059 C > T H687Y* 17709 MissenseC-Terminal 1 Exon 8 2078 T > C L693P* 17728 Missense C-Terminal 1 Exon 82131 A > G 1711V* 17781 Missense C-Terminal 1 Exon 8 2145 G > A A715A*17795 Silent/Splice C-Terminal 3 Intron 8 2146 − 2 A > G 18294 Splicesite C-Terminal 1 Exon 9 2156delG K718fs + 13X* 18306 Frame shiftC-Terminal 1 Exon 9 2182 A > T I728F* 18332 Missense C-Terminal 2 Exon 92230 C > T R744X 18380 Nonsense cNBD 4 Exon 9 2246 G > T G749V* 18396Missense cNBD 1 Exon 9 2260_2270dup A753fs + 6X* 18410 Frame shift cNBD1 GCCTTCGGGCC Exon 9 2271 G > C K757N* 18421 Missense cNBD 1 Exon 9 2299G > T D767Y* 18449 Missense cNBD 1 Exon 9 2309 T > C V770A* 18459Missense cNBD 1 Exon 9 2320 G > T D774Y 18470 Missense cNBD 1 Exon 92362 G > A E788K* 18512 Missense cNBD 1 Exon 9 2371_2397delCG 791_799del18521 In-frame del cNBD 1 GGGCGACGTCG RGDVVVAIL* TCGTGGCCATC CTG Exon 92371 C > T R791W 18521 Missense cNBD 1 Intron 9 2398 + 1 G > T 18549Splice site cNBD 3 Intron 9 2398 + 5 G > T 18553 Splice site cNBD 4 Exon10 2417 G > A G806E* 19685 Missense cNBD 1 Exon 10 2419delG G806fs + 2X*19687 Frame shift cNBD 1 Exon 10 2464 G > A V822M 19732 Missense cNBD 1Exon 10 2467 C > T R823W 19735 Missense cNBD 5 Exon 10 2494 A > T K832X*19762 Nonsense cNBD 1 Exon 10 2509 G > T D837Y* 19777 Missense cNBD 1Exon 10 2536 C > T P846S* 19804 Missense C-Terminal 1 Exon 10 2587 C > TR863X 19855 Nonsense C-Terminal 3 Exon 11 2653 C > T R885C 20233Missense C-Terminal 1 Exon 11 2660_2664ins K886fs + 88X* 20240 Frameshift C-Terminal 2 CAAGC Exon 11 2680 C > T R894C* 20260 MissenseC-Terminal 1 Exon 11 2681_2685dup R893fs + 81X* 20261 Frame shiftC-Terminal 1 CAGGC Exon 11 2681 G > T R894L* 20261 Missense C-Terminal 1Intron 11 2692 + 1_2962 + 20273 Splice site C-Terminal 1 6insACACGG Exon12 2707 G > A G903R* 20852 Missense C-Terminal 3 Exon 12 2717 C > TS906L* 20862 Missense C-Terminal 2 Exon 12 2722_2725dup A907fs + 12X*20867 Frame shift C-Terminal 1 GGCC Exon 12 2729_2744del G909fs + 58X*20874 Frame shift C-Terminal 1 CGGGCCGGGCG GGGGC Exon 12 2736_2751delR912fs + 55X* 20881 Frame shift C-Terminal 1 GGCGGGGGCA GGGCCG Exon 122738 C > T A913V 20883 Missense C-Terminal 5 Exon 12 2739dupCGGGCG914fs + 60X* 20884 Frame shift C-Terminal 1 Exon 12 2758 C > T R920W*20903 Missense C-Terminal 1 Exon 12 2759 G > A R920Q* 20904 MissenseC-Terminal 1 Exon 12 2765 G > A R922Q* 20910 Missense C-Terminal 1 Exon12 2771 G > A G924E* 20916 Missense C-Terminal 1 Exon 12 2771 G > CG924A* 20916 Missense C-Terminal 1 Exon 12 2780 G > A W927X 20925Nonsense C-Terminal 1 Exon 12 2784delG G928fs + 44X* 20930 Frame shiftC-Terminal 1 Exon 12 2810 G > A S937N* 20955 Missense C-Terminal 1 Exon12 2892delC P964fs + 8X* 21037 Frame shift C-Terminal 1 Exon 12 2893insCP964fs + 21038 Frame shift C-Terminal 1 153X* Exon 12 2918_2920insCCP972fs + 1X* 21063 Frame shift C-Terminal 1 Exon 12 2959_2960delCTP986fs + 130X 21104 Frame shift C-Terminal 1 Exon 13 3002insT F1000fs +21238 Frame shift C-Terminal 1 117X* Exon 13 3002 G > A W1001X 21238Nonsense C-Terminal 5 Exon 13 3014 G > A R1005Q* 21250 MissenseC-Terminal 1 Exon 13 3020 G > A R1007H* 21256 Missense C-Terminal 1 Exon13 3032delA Q1010fs + 21268 Frame shift C-Terminal 1 45X* Exon 13 3040C > T R1014X 21276 Nonsense C-Terminal 1 Exon 13 3088_3089dupGCS1029fs + 21324 Frame shift C-Terminal 1 27X* Exon 13 3093_3106delTCGR1033fs + 21329 Frame shift C-Terminal 1 GCGGCCCCGGG 79X* Exon 133093dupGGGT G1031fs + 21330 Frame shift C-Terminal 1 87X* Exon 133094delC G103lfs + 24X 21330 Frame shift C-Terminal 1 Exon 13 3097 C > TR1033W* 21333 Missense C-Terminal 1 Exon 13 3098insC R1032fs + 21334Frame shift C-Terminal 1 85X* Exon 13 3099_3112delGCC R1033fs + 21335Frame shift C-Terminal 1 CCGGGGCGACG 79X* Exon 13 3099delG P1034fs + 21X21335 Frame shift C-Terminal 1 Exon 13 3099_3100insCG R1033fs + 21335Frame shift C-Terminal 1 23X* Exon 13 3100_3107delCCC R1033fs + 21336Frame shift C-Terminal 1 CGGGGinsGGC 82X* Exon 13 3101_3108delCCCR1033fs + 21337 Frame shift C-Terminal 1 GGGGC 81X* Exon 133101_3103insGGC 1034msR* 21337 In-frame ins C-Terminal 1 Exon 133102_3111delCCG P1034fs + 21338 Frame shift C-Terminal 1 GGGCGAC 18X*Exon 13 3103delC P1034fs + 21X 21339 Frame shift C-Terminal 2 Exon 133104insC P1034fs + 21340 Frame shift C-Terminal 2 83X* Exon 13 3108insGG1036fs + 81X 21344 Frame shift C-Terminal 3 Exon 13 3112 G > A V1038M*21348 Missense C-Terminal 1 Exon 13 3113_3126dup D1037fs + 21349 Frameshift C-Terminal 1 GCCCCGGGG 23X* CGACG Exon 13 3146 T > C L1049P* 21382Missense C-Terminal 1 Exon 14 3196 C > G L1066V* 21705 MissenseC-Terminal 1 Exon 14 3233 A > G Y1078C* 21742 Missense C-Terminal 1 Exon14 3234delC A1077fs + X* 21743 Frame shift C-Terminal 1 Exon 14 3256insGG1085fs + 21765 Frame shift C-Terminal 1 32X* Exon 14 3278 C > T P1093L*21787 Missense C-Terminal 2 Exon 15 3343 A > G M1115V* 23214 MissenseC-Terminal 1 Exon 15 3407_3410dup R1135fs + 23278 Frame shift C-Terminal1 CGCC 134X* Exon 15 3471insC G1158fs + 23342 Frame shift C-Terminal 1110X* *denotes a novel variant, unique to this cohort. Deletion variantsare indicated as “del”, insertions as ins, duplications as “dup”, andframeshift mutations are designated by “fs”.

TABLE 3 Summary of putative LQT3-associated mutations in SCN5A Positionin SEQ ID Mutation No. of Region Nucleotide Variant NO: 3 Type Locationpatients Exon 2 53 G > A R18Q* 141435 Missense N-terminal 1 Exon 2 80G > A R27H 141408 Missense N-terminal 1 Exon 2 89 A > G E30G* 141399Missense N-terminal 1 Exon 2 128 G > A R43Q 141360 Missense N-terminal 1Exon 2 142 G > A E48K* 141346 Missense N-terminal 1 Exon 2 154 C > TP52S* 141334 Missense N-terminal 1 Exon 2 158 G > A R53Q* 141330Missense N-terminal 1 Exon 2 217 C > T Q73X* 141271 Nonsense N-terminal1 Exon 3 310 C > G R104G* 138573 Missense N-terminal 1 Exon 3 343 A > GS115G* 138540 Missense N-terminal 1 Exon 3 373 G > C V125L 138510Missense N-terminal 1 Exon 5 535 C > T R179X 129099 Nonsense DI-S2/S3 1Exon 6 635 T > C L212P 121991 Missense DI-S3/S4 1 Exon 6 664 C > T R222X121962 Nonsense DI-S4 1 Exon 6 665 G > A R222Q* 121961 Missense DI-S4 1Exon 6 673 C > T R225W 121953 Missense DI-S4 4 Exon 7 718 G > A V240M*118130 Missense DI-S4/S5 1 Exon 7 739 G > C V247L* 118109 MissenseDI-S4/S5 1 Exon 7 825 C > A N275K 118023 Missense DI-S5 1 Exon 7 865 G >A G289S* 117983 Missense DI-S5/S6 1 Exon 9 1018 C > T R340W* 114971Missense DI-S5/S6 1 Exon 9 1099 C > T R367C 114890 Missense DI-S5/S6 2Exon 9 1109 C > T T370M 114880 Missense DI-S5/S6 1 Exon 10 1167 C > AY389X* 114302 Nonsense DI-S5/S6 1 Exon 10 1190 T > C I397T* 114279Missense DI-S6 1 Exon 10 1218 C > G N406K 114251 Missense DI-S6 1 Exon10 1225 C > G L409V* 114244 Missense DI-S6 1 Exon 10 1231 G > A V411M114238 Missense DI-S6 3 Exon 10 1285_1287delGAG 429delE* 114182 In-framedel DI/DII 1 Exon 11 1385 A > C E462A* 113042 Missense DI/DII 1 Exon 121588 T > G F530V* 112194 Missense DI/DII 1 Exon 12 1604 G > A R535Q*112178 Missense DI/DII 2 Exon 12 1705 C > T R569W* 112077 MissenseDI/DII 1 Exon 12 1712 G > T S571I* 112070 Missense DI/DII 1 Exon 12 1714G > T A572S* 112068 Missense DI/DII 2 Exon 12 1715 C > T A572V* 112067Missense DI/DII 2 Exon 12 1756_1761delGCCCTC 586_587delAL* 112021In-frame del DI/DII 1 Exon 12 1844 G > A G615E 111938 Missense DI/DII 5Exon 13 1915 G > A G639R 107206 Missense DI/DII 1 Exon 13 1960 G > AE654K* 107161 Missense DI/DII 1 Exon 13 2018 T > C L673P* 107103Missense DI/DII 1 Exon 14 2065 C > T R689C* 106106 Missense DI/DII 1Exon 14 2102 C > T P701L 106069 Missense DI/DII 1 Exon 14 2192 C > TT731I* 105979 Missense DII-S1 1 Exon 14 2249 A > G Q750R* 105922Missense DII-S2 1 Exon 15 2314 G > A D772N 95702 Missense DII-S2/S3 1Exon 16 2447 T > A F816Y* 94211 Missense DII-S4 1 Exon 16 2542 A > TI848F* 94116 Missense DII-S5 1 Exon 16 2552_2553dupGT V850fs + 18X*94107 Frame shift DII-S5 1 Exon 17 2878 C > A Q960K* 89461 MissenseDII/DIII 1 Exon 17 2894 G > T R965L* 89445 Missense DII/DIII 1 Exon 172942 G > T C981F* 89397 Missense DII/DIII 1 Exon 17 2989 G > T A997S89350 Missense DII/DIII 1 Exon 17 3010 T > C C1004R* 89329 MissenseDII/DIII 1 Exon 17 3157 G > A E1053K 89182 Missense DII/DIII 1 Exon 173206 C > T T1069M 89133 Missense DII/DIII 1 Exon 18 3299 C > T A1100V*87605 Missense DII/DIII 1 Exon 18 3340 G > A D1114N 87564 MissenseDII/DIII 1 Exon 19 3496 G > A D1166N* 84856 Missense DII/DIII 1 Exon 203596 A > C Y1199S* 83547 Missense DII/DIII 1 Exon 20 3634_3636delATC1212delI* 83507 In-frame del DIII-S1 1 Exon 22 3847 C > A L1283M* 70711Missense DIII-S3 1 Exon 22 3911 C > T T1304M 70647 Missense DIII-S4 3Exon 23 3974 A > G N1325S 68598 Missense DIII-S4/S5 3 Exon 23 3976 G > TA1326S* 68596 Missense DIII-S4/S5 1 Exon 23 4000 A > G I1334V* 68572Missense DIII-S4/S5 1 Exon 23 4012 C > G L1338V* 68560 Missense DIII-S51 Exon 24 4296 G > C R1432S 65414 Missense DIII-S5/S6 1 Exon 25 4415 A >G N1472S* 64643 Missense DIII/DIV 1 Exon 25 4418 T > G F1473C 64640Missense DIII/DIV 1 Exon 26 4442 G > A G1481E 63936 Missense DIII/DIV 1Exon 26 4459 A > C M1487L* 63919 Missense DIII/DIV 1 Exon 26 4463 C > GT1488R* 63915 Missense DIII/DIV 1 Exon 26 4467 G > T E1489D* 63911Missense DIII/DIV 1 Exon 26 4478 A > G K1493R 63900 Missense DIII/DIV 2Exon 26 4484 A > C Y1495S* 63894 Missense DIII/DIV 1 Exon 26 4492 A > GM1498V* 63886 Missense DIII/DIV 1 Exon 26 4501 C > G L1501V 63877Missense DIII/DIV 1 Exon 26 4515 G > T K1505N* 63863 Missense DIII/DIV 1Exon 26 4519_4527delCAGAAGCCC 1507_1509delQKP 63851 In-frame delDIII/DIV 1 Exon 27 4594 G > A V1532I* 62678 Missense DIV-S1 1 Exon 274680 G > C L1560F* 62592 Missense DIV-S2 1 Exon 27 4779 C > G I1593M*62493 Missense DIV-S3 1 Exon 27 4781 T > C F1594S* 62491 Missense DIV-S31 Exon 27 4786 T > A F1596I* 62486 Missense DIV-S3 2 Exon 284850_4852delTCT 1617delF 59700 In-frame del DIV-S3/S4 1 Exon 28 4868 G >A R1623Q 59684 Missense DIV-S4 2 Exon 28 4868 G > T R1623L 59684Missense DIV-S4 1 Exon 28 4877 G > A R1626H 59675 Missense DIV-S4 1 Exon28 4930 C > T R1644C 59622 Missense DIV-S4 1 Exon 28 4948 C > T L1650F*59604 Missense DIV-S4/S5 1 Exon 28 4955 T > C M1652T* 59597 MissenseDIV-S4/S5 1 Exon 28 5168 C > A T1723N* 59384 Missense DIV-S5/S6 1 Exon28 5215 C > T R1739W* 59337 Missense DIV-S5/S6 1 Exon 28 5281 C > TL1761F* 59271 Missense DIV-S6 1 Exon 28 5282 T > A L1761H* 59270Missense DIV-S6 1 Exon 28 5287 G > A V1763M 59265 Missense DIV-S6 1 Exon28 5329 G > A V1777M 59223 Missense C-Terminal 1 Exon 28 5336 C > TT1779M 59216 Missense C-Terminal 2 Exon 28 5350 G > A E1784K 59202Missense C-Terminal 15 Exon 28 5361_5364del TGAG L1786fs + 45X* 59188Frame shift C-Terminal 1 Exon 28 5384 A > G Y1795C 59168 MissenseC-Terminal 1 Exon 28 5393 G > A W1798X* 59159 Nonsense C-Terminal 1 Exon28 5477 G > A R1826H 59075 Missense C-Terminal 2 Exon 28 5516 A > GD1839G 59036 Missense C-Terminal 1 Exon 28 5689 C > T R1897W* 58863Missense C-Terminal 1 Exon 28 5701 G > C E1901Q* 58851 MissenseC-Terminal 1 Exon 28 5929 T > A Y1977N* 58623 Missense C-Terminal 1 Exon28 6010 T > G F2004V* 58542 Missense C-Terminal 1 Exon 28 6034 C > TR2012C* 58518 Missense C-Terminal 1 *denotes a novel variant, unique tothis cohort. Deletion variants are indicated as “del”, duplications as“dup”, and frameshift mutations are designated by “fs”.

TABLE 4 Summary of putative LQT5-associated mutations in KCNE1 Positionin SEQ ID Mutation No. of Region Nucleotide Variant NO: 4 Type Locationpatients Exon 4 9_12delGTCT L3fs + 4X* 13137 Frame shift N-Terminal 1Exon 4 13insT S4fs + 0X* 13134 Frame shift N-Terminal 1 Exon 4 23 C > TA8V 13123 Missense N-Terminal 1 Exon 4 29 C > T T10M 13117 MissenseN-Terminal 3 Exon 4 50 G > A W17X* 13096 Nonsense N-Terminal 1 Exon 4 83C > T S28L 13063 Missense N-Terminal 2 Exon 4 95 G > A R32H 13051Missense N-Terminal 1 Exon 4 163 G > A G55S* 12983 MissenseTransmembrane 1 Exon 4 172 A > C T58P 12974 Missense Transmembrane 2Exon 4 176 T > C L59P 12970 Missense Transmembrane 2 Exon 4 199 C > TR67C* 12947 Missense C-Terminal 1 Exon 4 200 G > A R67H* 12946 MissenseC-Terminal 1 Exon 4 209 A > T K70M* 12937 Missense C-Terminal 1 Exon 4226 G > A D76N 12920 Missense C-Terminal 9 Exon 4 227_229delACCinsTCTAN75fs + 34X* 12917 Frame shift C-Terminal 1 Exon 4 247 G > A E83K* 12899Missense C-Terminal 1 Exon 4 349 C > T Q117X* 12797 Nonsense C-Terminal1 Exon 4 374 C > T T125M 12772 Missense C-Terminal 1 *denotes a novelvariant, unique to this cohort. Deletion variants are indicated as“del”, insertion as “ins”, and frameshift mutations are designated by“fs”.

TABLE 5 Summary of putative LQT6-associated mutations in KCNE2 Positionin SEQ ID Mutation No. of Region Nucteotide Variant NO: 5 Type Locationpatients Exon 2 40 G > A V14I 15735 Missense N-Terminal 1 Exon 2 59 T >A I20N* 15754 Missense N-Terminal 1 Exon 2 80 G > A R27H* 15775 MissenseN-Terminal 1 Exon 2 161 T > C M54T 15856 Missense Transmembrane 3 Exon 2170 T > C I57T 15865 Missense Transmembrane 2 Exon 2 193 G > C V65L*15888 Missense Transmembrane 1 Exon 2 230 G > A R77Q 15925 MissenseC-Terminal 2 Exon 2 281 A > G E94G* 15976 Missense C-Terminal 1 Exon 2369_370delCT P123fs + 14X* 16064 Frame shift C-Terminal 1 *denotes anovel variant, unique to this cohort. Deletion variants are indicated as“del” and frameshift mutations are designated by “fs”.

REFERENCES

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EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims. The contents of allreferences, patents and published patent applications cited throughoutthis application are incorporated herein by reference.

What is claimed is:
 1. A method for identifying whether a subjectsuffers from or is predisposed to suffer from congenital long QTsyndrome (LQTS) comprising identifying the presence of at least onebiomarker in a biological sample obtained from the subject, wherein thebiomarker is selected from the group consisting of variants set forth inTables 1-5.
 2. The method of claim 1, wherein the biomarker is a variantin at least one of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1or KCNE2 genes.
 3. The method of claim 1, wherein the variant isselected from the group consisting of a mutation, a missense mutation, anonsense mutation, an insertion, a deletion, or a frameshift mutation.4. The method of claim 1, wherein the variant disrupts the open readingframe of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
 5. The method ofclaim 1, wherein the variant disrupts the canonical splice site of theKCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
 6. The method of claim 5,wherein the variant disrupts the splice acceptor sequence and/or thesplice donor recognition sequence of the KCNQ1, KCNH2, SCN5A, KCNE1 orKCNE2 genes.
 7. The method of claim 1, wherein the biomarker is selectedfrom the group consisting of a L266P mutation in KCNQ1, a R518X mutationin KCNQ1, a R594Q mutation in KCNQ1, a G168R mutation in KCNQ1, a E1784Kmutation in SCN5A, a Q73X nonsense mutation in SCN5A, a R179X nonsensemutation in SCN5A, a R222X nonsense mutation in SCN5A, a Y389X nonsensemutation in SCN5A, and a W1798X nonsense mutation in SCN5A, a V850fs+18Xframeshift mutation in SCN5A and a L1786fs+45X frameshift mutation inSCN5A.
 8. The method of claim 1, wherein the biomarker is a variantidentified with an asterisk in Table 1-5.
 9. A method for predictingtherapeutic responsiveness of a subject having LQTS or susceptible tohaving LQTS to LQTS therapy, the method comprising determining thepresence or absence of at least one biomarker in a biological sampleobtained from the subject, wherein the biomarker is selected from thegroup consisting of variants set forth in Tables 1-5, and wherein thepresence of the at least one biomarker in the sample is an indicationthat the subject will respond to the LQTS therapy, thereby predictingresponsiveness of the subject to the LQTS therapy.
 10. The method ofclaim 9, wherein the LQTS therapy comprises a method selected from thegroup consisting of administration of beta receptor blocking agents,implantation of an implantable cardioverter-defibrillator (ICD),potassium supplementation, administration of a sodium channel blockersuch as mexiletine, and amputation of the cervical sympathetic chain.11. The method of claim 9, wherein determining the presence or absenceof at least one biomarker is accomplished using a technique selectedfrom the group consisting of polymerase chain reaction (PCR)amplification reaction, reverse-transcriptase PCR analysis,single-strand conformation polymorphism analysis (SSCP), mismatchcleavage detection, heteroduplex analysis, Southern blot analysis,Western blot analysis, deoxyribonucleic acid sequencing, restrictionfragment length polymorphism analysis, haplotype analysis, serotyping,and combinations or sub-combinations thereof, of said sample.
 12. Themethod of claim 9, wherein the sample from the subject is selected fromthe group consisting of a fluid, blood fluids, vomit, intra-articularfluid, saliva, lymph, cystic fluid, urine, fluids collected by bronchiallavage, fluids collected by peritoneal rinsing, gynecological fluids, ablood sample or a component thereof, a tissue or component thereof,bone, connective tissue, cartilage, lung, liver, kidney, muscle tissue,heart, pancreas, and skin.
 13. The method of claim 9, wherein thebiomarker is a variant in at least one of the KCNQ1 (LQT1), KCNH2(LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes.
 14. The method of claim 9,wherein the variant is selected from the group consisting of a mutation,a missense mutation, a nonsense mutation, an insertion, a deletion, or aframeshift mutation.
 15. The method of claim 9, wherein the variantdisrupts the open reading frame of the KCNQ1, KCNH2, SCN5A, KCNE1 orKCNE2 genes.
 16. The method of claim 9, wherein the variant disrupts thecanonical splice site, the splice acceptor sequence and/or splice donorrecognition sequence of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.17. The method of claim 1, wherein the biomarker is selected from thegroup consisting of a L266P mutation in KCNQ1, a R518X mutation inKCNQ1, a R594Q mutation in KCNQ1, a G168R mutation in KCNQ1, a E1784Kmutation in SCN5A, a Q73X nonsense mutation in SCN5A, a R179X nonsensemutation in SCN5A, a R222X nonsense mutation in SCN5A, a Y389X nonsensemutation in SCN5A, and a W1798X nonsense mutation in SCN5A, a V850fs+18Xframeshift mutation in SCN5A and a L1786fs+45X frameshift mutation inSCN5A.
 18. The method of claim 9, wherein the biomarker is a variantidentified with an asterisk in Table 1-5.
 19. A nucleic acid moleculecomprising a variant of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3),KCNE1 or KCNE2 genes selected from the group consisting of the variantsset forth in Tables 1-5.
 20. The nucleic acid molecule of claim 19,wherein the variant is identified with an asterisk in Table 1-5.